Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis
Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis
复制标题
多重定量分析LAG-3、FGL1、PD-L1和CD8 T细胞在肝细胞癌中的表达及临床意义
DOI：
10.1186/s12967-020-02469-8
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发表时间：
2020-08-06
影响因子：
7.4
通讯作者：
Xia, Jinglin
中科院分区：
文献类型：
--
作者：
Guo, Mengzhou;Yuan, Feifei;Xia, Jinglin
纤维蛋白样蛋白1（FGL 1）-淋巴细胞激活基因3（LAG-3）通路是一种很有前途的免疫靶点，与程序性死亡1（PD-1）/程序性死亡配体1（PD-L1）具有协同作用。然而，FGL 1-LAG-3通路在肝细胞癌（HCC）中的预后意义以及与PD-L1的相关性仍不清楚。方法采用多重免疫荧光法检测143例HCC患者血清中LAG-3、FGL 1、PD-L1和细胞毒性T细胞（CD 8（+）T）水平。研究了该标志物的表达与临床意义之间的关系。结果肝癌组织中FGL 1、LAG-3密度较癌旁正常肝组织高，PD-L1、CD 8密度较癌旁正常肝组织低。高水平的FGL 1与高密度的LAG-3（+）细胞密切相关，但与PD-L1无关。CD 8（+）T细胞密度与PD-L1水平呈正相关，与FGL 1表达呈负相关。LAG-3（+）细胞密度升高和CD 8（+）T细胞水平降低与疾病预后不良相关。此外，LAG-3（+）细胞恶化了基于CD 8（+）T细胞丰度的患者分层。肿瘤细胞上PD-L1表达阳性（PD-L1 TC+）的患者的生存率往往高于肿瘤细胞上PD-L1表达阴性（PD-L1 TC-）的患者。此外，PD-L1 TC（-）与高密度LAG-3（+）细胞的组合显示出最差的预后，而PD-L1 TC（+）与低密度LAG-3（+）细胞的患者具有最好的预后。结论LAG-3、FGL 1、PD-L1和CD 8在组织中有不同的分布，且相互之间存在一定的关系。高水平的LAG-3（+）细胞和CD 8（+）T细胞分别代表HCC的不利和有利预后生物标志物。
Background Fibrinogen-like protein 1 (FGL1)-Lymphocyte activating gene 3 (LAG-3) pathway is a promising immunotherapeutic target and has synergistic effect with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1). However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unknown. Methods The levels of LAG-3, FGL1, PD-L1 and cytotoxic T (CD8(+)T) cells in 143 HCC patients were assessed by multiplex immunofluorescence. Associations between the marker's expression and clinical significances were studied. Results We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3(+)cells but not PD-L1. CD8(+)T cells densities had positive correlation with PD-L1 levels and negative association with FGL1 expression. Elevated densities of LAG-3(+)cells and low levels of CD8(+)T cells were correlated with poor disease outcome. Moreover, LAG-3(+)cells deteriorated patient stratification based on the abundance of CD8(+)T cells. Patients with positive PD-L1 expression on tumor cells (PD-L1 TC+) tended to have an improved survival than that with negative PD-L1 expression on tumor cells (PD-L1 TC-). Furthermore, PD-L1 TC(-)in combination with high densities of LAG-3(+)cells showed the worst prognosis, and PD-L1 TC(+)patients with low densities of LAG-3(+)cells had the best prognosis. Conclusions LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3(+)cells and CD8(+)T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively.